RhoA/ROCK activation by growth hormone abrogates p300/histone deacetylase 6 repression of Stat5-mediated transcription.
We demonstrate here that growth hormone (GH) stimulates the activation of RhoA and its substrate Rho kinase (ROCK) in NIH-3T3 cells. GH-stimulated formation of GTP-bound RhoA requires JAK2-dependent dissociation of RhoA from its negative regulator p190 RhoGAP. Inactivation of RhoA does not affect GH-stimulated JAK2 tyrosine phosphorylation nor p44/42 MAPK ... activity. However, RhoA and ROCK activities are required for GH-stimulated, Stat5-mediated transcription. RhoA-dependent enhancement of GH-stimulated, Stat5-mediated transcription is due to repression of histone deacetylase 6 activity recruited by transcription cofactor p300 that negatively regulates GH-stimulated, Stat5-mediated transcription. We also demonstrate that RhoA is the pivot for cAMP-dependent protein kinase inhibition of GH-stimulated, Stat5-mediated transcription as a consequence of cAMP-dependent protein kinase inactivation of RhoA through serine residue 188 of RhoA. We have therefore provided a novel mechanism by which a Ras-like small GTPase, RhoA, can regulate Stat5-mediated transcription.
Mesh Terms:
Animals, Blotting, Western, Cell Division, Cell Nucleus, Cyclic AMP, DNA, Enzyme Activation, Genes, Reporter, Genetic Vectors, Growth Hormone, Histone Deacetylases, Humans, Intracellular Signaling Peptides and Proteins, Janus Kinase 2, Luciferases, Mice, Microscopy, Fluorescence, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Models, Biological, NIH 3T3 Cells, Phosphorylation, Precipitin Tests, Protein Binding, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Recombinant Proteins, STAT5 Transcription Factor, Serine, Time Factors, Transcription, Genetic, rho-Associated Kinases, rhoA GTP-Binding Protein
Animals, Blotting, Western, Cell Division, Cell Nucleus, Cyclic AMP, DNA, Enzyme Activation, Genes, Reporter, Genetic Vectors, Growth Hormone, Histone Deacetylases, Humans, Intracellular Signaling Peptides and Proteins, Janus Kinase 2, Luciferases, Mice, Microscopy, Fluorescence, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinases, Models, Biological, NIH 3T3 Cells, Phosphorylation, Precipitin Tests, Protein Binding, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Recombinant Proteins, STAT5 Transcription Factor, Serine, Time Factors, Transcription, Genetic, rho-Associated Kinases, rhoA GTP-Binding Protein
J. Biol. Chem.
Date: Jul. 30, 2004
PubMed ID: 15102857
View in: Pubmed Google Scholar
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